The aim of this project is to evaluate the antiarrhythmic, and electrocardiographic (ECG) effects, the pharmacokinetics, and the biologic effects of the tricyclic antidepressants (TCAs): imipramine, nortriptyline, and doxepin. Recently, in a clinical outcome study of depression, we showed that therapeutic plasma concentrations of imipramine produce predictable ECG effects, i.e., prolong the PR, QRS, and QTc invervals and lower T wave amplitude. Moreover, we discovered imipramine is antiarrhythmic against ventricular premature depolarizations (VPDs). These observations coupled with a long half-life of elimination, and minimal untoward side effects suggest imipramine or another TCA will be an important antiarrhythmic agent for cardiac patients. The efficacy of TCAs against VPDs in cardiac patients will be evaluated in an acute dose ranging study. Daily 24-hour ECG monitoring will document the effect of the TCAs on heart rate, frequency of VPDs and ECG intervals. Radionuclide angiography will be performed to assess the effects of TCAs on left ventricular function. The effect of exercise on the heart rate, blood pressure, and functional aerobic capacity of cardiac patients taking TCAs will be evaluated by exercise treadmill tests. Pharmacokinetics studies will be conducted to determine: 1) the plasma time course of imipramine and its cardioactive metabolites: desmethylimipramine, 2-hydroxyimipramine, and 2-hydroxydesmethylimipramine; 2) imipramine's half-life of elimination, metabolism, excretion, and "first-pass" effect; and 3) appropriate dosing schedules. There is a very high likelihood these studies will identify an outstanding new class of antiarrhythmic drugs for chronic oral therapy in cardiac patients.